Migraine is one of the most common neurological disorders in the US, and is among the top 20 causes of disability worldwide. The one-year prevalence of migraine headache in the United States is estimated to range from 8-15% overall affecting approximately three times more women than men. The estimated national direct cost burden of migraine is $11 billion per year, with an additional $6 billion of indirect costs. Migraie is a complex disorder with both genetic and environmental origins, however the precise mechanisms of the condition remain unclear. Recent studies have implicated potential gene associations with migraine, but the overall findings are inconsistent. More research is needed to elucidate these genetic and environmental pathways. Study Aims: The primary aim of this proposed study is to identify common genetic variants for migraine to determine whether there are single nucleotide polymorphisms (SNPs) associated with migraine. We will apply genome-wide association study (GWAS) methodology to compare Kaiser Permanente Northern California (KPNC) members with migraine to a control group of unaffected members. Secondary aims include replication in independent samples, analysis by subgroups of co-morbidity, candidate gene analysis of 4 putative SNPs/markers, comparison of telomere length between the two groups, and a sensitivity analysis of phenotyping strategies. Methods: Subjects will be drawn from the 110,266 fully genotyped participants in the KPNC Research Program on Genes, Environment, and Health (RPGEH). By using previously developed methods for identification of migraine in conjunction with a validation questionnaire mailed to a randomly selected subset, we plan to accurately capture patients who suffer from migraine, as well as a set of comparable controls. We will then perform a GWAS comparing migraine patients with non-headache controls to identify genetic variants associated with migraine both overall and within subgroups of race/ethnicity. After we have determined a set of significant SNPs, we will test these SNPs in subgroups of co-morbidity and replicate our findings in two independent migraine cohorts. Two additional proposed analyses include replication of previously established SNPs in our RPGEH cohort, and comparison of telomere length between the two groups. Summary: Performing GWAS to identify new candidate genes for migraine, testing previously-identified genes, and comparing telomere lengths are all important steps towards understanding the genetic underpinnings of migraine. Completing these proposed analyses in our large diverse study population will yield robust results that will be generalizable to the wider U.S. population. PUBLIC HEALTH RELEVANCE: Migraine is a common and complex disorder with both genetic and environmental origins, however, the precise mechanisms of the condition remain unclear. Recent studies have implicated genes associated with rare types of migraine, but the findings for common and classic migraine are inconsistent, possibly due to differences by subgroup of co-morbidity resulting in population stratification and confounding. In order to address these potential issues, we request funding to study the genetics underlying migraine in a large population-based cohort using both a GWA approach and testing candidate genes within subgroups of co-morbidity.